Although cortical and hippocampal GABAergic inhibitory interneurons represent only 20% of the total cortical cell population their anatomical diversity is unparalleled in the mammalian central nervous system; for example there are currently upwards of 20 acknowledged distinct members within the CA1 hippocampal formation alone. Their anatomical diversity is rich, with the morphologies of many cell types remaining local to a particular subfield, while other cell types extend wide arbor dendrites and axons that cross numerous cortical and hippocampal layers and subfields. Inhibitory interneurons often demonstrate exquisite targeting of their axons to differential postsynaptic structures. For example, axons can target selective subcellular domains (e.g. the perisomatic, axon initial segment or specific dendritic domains) to compartmentalize or time electrical activity in either a positive or negative manner. Alternatively, axons can make projections several millimeters in length, to innervate thousands of postsynaptic targets to co-ordinate the activity of both homogeneous and distributed neuronal ensembles. Moreover, each cortical interneuron subtype is unique in its proliferative history, migration during corticogenesis as well as postnatal integration into cortical circuitry. Indeed several developmentally regulated neural circuit disorders such as epilepsy, schizophrenia and autism are likely associated with deficits in the numbers and function of distinct interneuron cohorts. For all of these reasons inhibitory interneurons have recently become the intense focus of investigators drawn from a wide variety of backgrounds. Over the last two decades, work from my lab has contributed to a rapidly expanding body of literature demonstrating that the properties of both afferent (excitatory and inhibitory) and efferent synaptic drive, the repertoire of intrinsic voltage-gated conductances and downstream signaling cascades often differ between subpopulations of local circuit inhibitory interneurons. Moreover, these properties are often intimately linked to the particular function each cell type plays within its respective network. As a result it has become clear that to elucidate the role(s) played by well-defined subpopulations of inhibitory neurons in a particular brain function or pathology, each of these parameters must be carefully and systematically studied. To this end, work in my Section over the last year has largely focused on two main aspects of inhibitory interneuron function: (1) We have continued our study of glutamatergic and GABAergic synaptic transmission made onto inhibitory interneurons and their downstream targets within the hippocampal formation. (2) We are also using genetic approaches to examine the embryogenesis, migration and development of specific cohorts of medial- and caudal-ganglionic eminence derived hippocampal and cortical GABAergic inhibitory interneurons. We have also commenced investigation into the developmental trajectories of identified cortical principal cells. specifically we are interested in determining whether specific pyramidal cells of deep cortical layers have a preferential wiring with specific inhibitory interneuron subtypes. We have also begun to extend our studies to include investigation into hippocampal and cortical circuits in human resected tissue. This multi-parametric approach of cortical and hippocampal development has been extremely fruitful and is a perfect example of a research strategy well suited to the intramural environment. Having the flexibility to pursue this line of research would not have been possible without the support of the NIH intramural program. Genetic specification, development, and circuit function of inhibitory interneurons Although vastly outnumbered, inhibitory interneurons critically pace and synchronize excitatory principal cell populations to coordinate cortical information processing. Precision in this control relies upon a remarkable diversity of interneurons primarily determined during embryogenesis by genetic restriction of neuronal potential at the progenitor stage. Like their neocortical counterparts, hippocampal interneurons arise from medial and caudal ganglionic eminence (MGE and CGE) precursors. However, while studies of the early specification of neocortical interneurons are rapidly advancing similar lineage analyses of hippocampal interneurons have lagged. In the previous cycle we performed a hippocampocentric investigation of interneuron lineage analysis using transgenic mice that specifically reported MGE- and CGE- derived interneurons either constitutively or inducibly. Hippocampal interneurons arise during two neurogenic waves between E9-E12 and E12-E16 from MGE and CGE, respectively. These cells migrate through the marginal zone and subventricular zone to populate the hippocampus proper. In the mature hippocampus, CGE-derived interneurons primarily localize to superficial layers in strata lacunosum moleculare and deep radiatum, while MGE-derived interneurons readily populate all layers with preference for strata pyramidale and oriens. Combined molecular, anatomical, and electrophysiological interrogation of MGE/CGE-derived interneurons revealed that the MGE produces parvalbumin-, somatostatin-, and nitric oxide synthase-expressing interneurons including fast-spiking basket, bistratified, axo-axonic, oriens-lacunosum moleculare, neurogliaform, and ivy cells. In contrast, CGE-derived interneurons contain cholecystokinin, calretinin, vasoactive intestinal peptide, and reelin including non-fast-spiking basket, Schaffer collateral-associated, mossy fiber-associated, trilaminar, and additional neurogliaform cells. Our findings provided a basic blueprint of the developmental origins of hippocampal interneuron diversity. In this cycle we have interrogated further the rules of embryogenesis and development for specific cohorts of interneuron and linked this both to their glutamate receptor expression and overall function in the nascent network. Glutamate receptors in the mammalian central nervous system comprise three principal subclasses; AMPA, kainate and NMDA receptors. Together these surface expressed receptors control fast synaptic transmission throughout most of the CNS. Assembly and proper targeting of each class of receptor is an essential step toward establishing correct and balanced synaptic signaling throughout cortical networks. To this end the kainate-preffering subtype of glutamate receptors is intimately involved with an auxiliary protein class called NETOs. Although it is established that Netos auxiliary subunits are critical for kainate receptor (KAR) function, direct evidence for their regulation of native KARs is limited. Because Neto KAR regulation is GluK subunit/Neto isoform specific, such regulation must be determined in cell-type-specific contexts. We have recently demonstrated Neto1/2 expression in somatostatin (SOM)-, cholecystokinin/cannabinoid receptor 1 (CCK/CB1)-, and parvalbumin (PV)-containing interneurons of the hippocampal formation. KAR-mediated excitation of these interneurons is contingent upon Neto1 because kainate yields comparable effects in Neto2 knockouts and wild-types but fails to excite interneurons or recruit inhibition in Neto1 knockouts. In contrast, presynaptic KARs in CCK/CB1 interneurons are dually regulated by both Neto1 and Neto2. Neto association promotes tonic presynaptic KAR activation, dampening CCK/CB1 interneuron output, and loss of this brake in Neto mutants profoundly increases CCK/CB1 interneuron-mediated inhibition. Our results confirm that Neto1 regulates endogenous somatodendritic KARs in diverse interneurons and demonstrate Neto regulation of presynaptic KARs in mature inhibitory presynaptic terminals.